Phototherapy and DNA changes in full term neonates with hyperbilirubinemia

Background: Phototherapy has remained the standard therapeutic approach for neonatal hyperbilirubinemia. Oxidative effects of phototherapy on cell membranes and cell components may have a wide range of potential adverse effects, including enhanced lipid peroxidation and DNA damage. Apoptosis is an indispensable mechanism for maintaining many cellular functions, including cell replication, and removal of damaged cells with high burden of genetic mutations. Many genes function as apoptosis regulatory genes. Examples of these genes include the BCL2 gene which is an anti-apoptotic oncogene, and the BAX gene which acts as a promoter of apoptosis.Objectives: Assess the effect(s) of phototherapy on DNA and on the rate of apoptosis in full term neonates with hyperbilirubinemia. It comprised 35 neonates with indirect hyperbilirubinemia who received phototherapy for 48h, and 20 apparently healthy full term neonates with normal serum bilirubin level, as a control group. DNA damage was assessed by DNA fragmentation and micronucleus assay. Determination of the anti-apoptotic effect(s) of BCL2 gene was achieved by quantitative assay of its product, (BCL2) protein, by ELISA and BAX gene expression status was assessed by PCR.Results: The frequency of micronuclei in circulating lymphocytes of neonates who received phototherapy has significantly increased before and after phototherapy compared to controls, (p< 0.001; p< 0 0.00001), respectively. DNA fragmentation in circulating lymphocytes, was significantly higher among cases before and after phototherapy compared to controls (p< 0.0001; p< 0 0.00001). The plasma BCL2 protein was significantly lower in the cases before and after phototherapy compared to controls (p< 0.01; p <0.01), respectively, and BAX gene expression was significantly high among cases before and after phototherapy compared to controls.Conclusions: Geno toxic effects of bilirubin and phototherapy, induce more DNA damage and enhances apoptosis of exposed cells, probably through down regulation of BCL2 expression and upregulation of BAX gene expression in neonates with hyperbilirubinemia. Keywords: Hyperbilirubinemia; Phototherapy; DNA damage; Apoptosis; BCL2 gene; BAX gen

Oxidative Stress in Metabolic Disorders and Drug-Induced Injury: The Potential Role of Nrf2 and PPARs Activators

No abstract availabl

P193 USEFUL I: musculoskeletal ultrasound to identify patients with lupus arthritis with better response to therapy

Background In SLE, musculoskeletal manifestations have an impact on quality of life, disability and clinical trial outcomes, but are harder to assess than in RA and PsA. We previously showed that joint swelling lacks sensitivity, specificity and responsiveness compared to ultrasound. USEFUL was a multicentre longitudinal study to determine clinical features predicting ultrasound synovitis and whether patients with ultrasound synovitis respond better to therapy. Methods SLE patients were recruited if the referring physician deemed they had inflammatory pain warranting treatment. Swollen joints were not required. At baseline, physicians recorded the features that led them to diagnose inflammatory pain and features of concurrent fibromyalgia and osteoarthritis. Stable doses of prednisolone (≤5 mg/day), antimalarials or immunosuppressants were allowed. Participants received depomedrone 120 mg IM then were assessed at 0, 2 and 6 weeks for 66/68 swollen and tender joint counts, BILAG-2004, SLEDAI-2K, physician global and MSK-VAS, inflammatory markers, patient pain and disease activity-VAS, HAQ-DI, LupusQoL, ultrasound of hands and wrists (blinded to patient and clinical assessor). An internal pilot determined the primary endpoint: EMS-VAS at 2 weeks (adjusted for baseline) between patients with ultrasound-synovitis vs. normal ultrasound at baseline. Sensitivity analyses adjusted for prednisolone and immunosuppressants. Results 122/133 patients recruited completed all visits. There was significant disagreement between clinical examination and ultrasound. 78/133 had ultrasound synovitis; 68% of these had ≥1 swollen joint. Of 66/133 patients with ≥ 1 swollen joint, 20% had normal ultrasound. Ultrasound-synovitis was more likely with joint swelling, a symmetrical small joint distribution and active serology. Physician-determined EMS, other lupus features or prior response to therapy were not associated. Fibromyalgia or osteoarthritis did not reduce the probability of ultrasound synovitis. In the full analysis set (n=133) there was no difference in EMS VAS at 2 weeks according to ultrasound synovial status as baseline (difference -8 mm, 95% CI -19, 4 mm, p=0.178). 32 patients had fibromyalgia. After excluding these patients, we found a statistically and clinically significantly better clinical response to depomedrone in patients with ultrasound-synovitis at baseline (baseline-adjusted EMS VAS at 2 weeks -12 mm, 95% CI -24, 0 mm, p=0.049). This difference was greater in the treatment-adjusted sensitivity analysis (-12.8 (95% CI -22, -3 mm), p=0.007) and the per-protocol-adjusted sensitivity analysis (-14.8 mm (95% CI -20.8, -8.8 mm), p<0.001). Patient with ultrasound synovitis had higher rates of improvement in the musculoskeletal BILAG-2004 (56% vs. 26%, p=0.09) and SLEDAI-2K (37% vs. 15%, p=0.03). Conclusions In lupus arthritis distribution and serology, but not other features, help identify ultrasound-synovitis. Ultrasound-synovitis was independent of features of fibromyalgia, but fibromyalgia confounded assessment of response. Excluding fibromyalgia, response to therapy was better in patients with abnormal ultrasound compared to normal. Ultrasound should be used to select patients for therapy and clinical trials, especially when there are inflammatory symptoms without swollen joints

Cyclin A and cyclin D1 as significant prognostic markers in colorectal cancer patients

BACKGROUND: Colorectal cancer is a common cancer all over the world. Aberrations in the cell cycle checkpoints have been shown to be of prognostic significance in colorectal cancer. METHODS: The expression of cyclin D1, cyclin A, histone H3 and Ki-67 was examined in 60 colorectal cancer cases for co-regulation and impact on overall survival using immunohistochemistry, southern blot and in situ hybridization techniques. Immunoreactivity was evaluated semi quantitatively by determining the staining index of the studied proteins. RESULTS: There was a significant correlation between cyclin D1 gene amplification and protein overexpression (concordance = 63.6%) and between Ki-67 and the other studied proteins. The staining index for Ki-67, cyclin A and D1 was higher in large, poorly differentiated tumors. The staining index of cyclin D1 was significantly higher in cases with deeply invasive tumors and nodal metastasis. Overexpression of cyclin A and D1 and amplification of cyclin D1 were associated with reduced overall survival. Multivariate analysis shows that cyclin D1 and A are two independent prognostic factors in colorectal cancer patients. CONCLUSIONS: Loss of cell cycle checkpoints control is common in colorectal cancer. Cyclin A and D1 are superior independent indicators of poor prognosis in colorectal cancer patients. Therefore, they may help in predicting the clinical outcome of those patients on an individual basis and could be considered important therapeutic targets

ARID1B is a specific vulnerability in ARID1A-mutant cancers

Summary Recent studies have revealed that ARID1A is frequently mutated across a wide variety of human cancers and also has bona fide tumor suppressor properties. Consequently, identification of vulnerabilities conferred by ARID1A mutation would have major relevance for human cancer. Here, using a broad screening approach, we identify ARID1B, a related but mutually exclusive homolog of ARID1A in the SWI/SNF chromatin remodeling complex, as the number one gene preferentially required for the survival of ARID1A-mutant cancer cell lines. We show that loss of ARID1B in ARID1A-deficient backgrounds destabilizes SWI/SNF and impairs proliferation. Intriguingly, we also find that ARID1A and ARID1B are frequently co-mutated in cancer, but that ARID1A-deficient cancers retain at least one ARID1B allele. These results suggest that loss of ARID1A and ARID1B alleles cooperatively promotes cancer formation but also results in a unique functional dependence. The results further identify ARID1B as a potential therapeutic target for ARID1A-mutant cancers

Effects of Wartime Crisis Perceptions on the Effectiveness of Political Advertising: The Moderating Role of Political Involvement

This research examines how political advertising is operated in a volatile context, such as a state of war or instability. The study employed a self-completing cross-sectional survey to gather the data in the period of the 2016 Syrian elections for members of parliament. The research tested the hypothetical model and its equivalency related to political involvement through the use of structural equation modelling. The outcomes of the tests revealed the structure of belief as a four-dimensional variate. The four dimensions encapsulate information, veracity, sarcasm, and cynicism. In addition, perceptions during conflicts had a negative effect on attitude through sarcasm displayed by voters with low political involvement. The results also found that negative attitude had a link with lower degrees of veracity with regards to voters who are less involved but to greater degrees of cynicism highly politically active individuals. We found that less favourable attitudes to political advertising lowered the likelihoods for voters to watch political ads or announcements, support a runner, and be willing to go to the poll. We found no relation between the fact of paying attention to political advertising and intention of voters to use their ballot

Macrocytosis may be associated with mortality in chronic hemodialysis patients: a prospective study

<p>Abstract</p> <p>Background</p> <p>Macrocytosis occurs in chronic hemodialysis (CHD) patients; however, its significance is unknown. The purpose of this study was to establish the prevalence and distribution of macrocytosis, to identify its clinical associations and to determine if macrocytosis is associated with mortality in stable, chronic hemodialysis patients.</p> <p>Methods</p> <p>We conducted a single-centre prospective cohort study of 150 stable, adult CHD patients followed for nine months. Macrocytosis was defined as a mean corpuscular volume (MCV) > 97 fl. We analyzed MCV as a continuous variable, in tertiles and using a cutoff point of 102 fl.</p> <p>Results</p> <p>The mean MCV was 99.1 ± 6.4 fl, (range 66-120 fl). MCV was normally distributed. 92 (61%) of patients had an MCV > 97 fl and 45 (30%) > 102 fl. Patients were not B12 or folate deficient in those with available data and three patients with an MCV > 102 fl had hypothyroidism. In a logistic regression analysis, an MCV > 102 fl was associated with a higher Charlson-Age Comorbidity Index (CACI) and higher ratios of darbepoetin alfa to hemoglobin (Hb), [(weekly darbepoetin alfa dose in micrograms per kg body weight / Hb in g/L)*1000]. There were 23 deaths at nine months in this study. Unadjusted MCV > 102 fl was associated with mortality (HR 3.24, 95% CI 1.42-7.39, P = 0.005). Adjusting for the CACI, an MCV > 102 fl was still associated with mortality (HR 2.47, 95% CI 1.07-5.71, P = 0.035).</p> <p>Conclusions</p> <p>Macrocytosis may be associated with mortality in stable, chronic hemodialysis patients. Future studies will need to be conducted to confirm this finding.</p

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO